Predicting students’ academic performance has long been an important area of research in education. Most existing literature have made use of traditional statistical methods that run into the problems of overfitted models, inability to effectively handle large numbers of participants and predictors, and inability to pick out non-linearities that may be present. Regression-based ML methods that can produce highly interpretable yet accurate models for new predictions, are able to provide some solutions to the aforementioned problems. The present study is the first study that develops and compares between traditional MLR methods and regression-based ML methods (i.e. ridge regression, LASSO regression, elastic net, and regression trees) to predict students’ science performance in the PISA 2015. A total of 198,712 students from 60 countries, and 66 student- and school-related predictors were used to develop the predictive models. Predictive accuracy of the various models built were not that different, however, there were significant differences in the predictors identified as most important by the different methods. Although regression-based ML techniques did not outperform traditional MLR, significant advantages for using ML methods were noted and discussed. Moving forward, we strongly believe that there is merit for using such regression-based ML methods in educational research. Educational research can benefit from adopting ML practices and methods to produce models that can not only be used for explaining factors that influence academic performance prediction, but also for making more accurate predictions on unseen data.